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ORIGINAL RESEARCH |
From Merck Research Labs, Rahway, New Jersey and SCIREX Corp., Austin, Texas.
Address reprint requests to: Briggs W. Morrison, MD 126 East Lincoln Avenue PO Box 2000 RY32-641 Rahway, NJ 07065 E-mail: briggs_morrison{at}merck.com
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Abstract |
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Methods: A double-masked, randomized, placebo and active-comparator–controlled clinical trial including 127 subjects with histories of primary dysmenorrhea was conducted in an outpatient clinical research center. Subjects were randomly assigned to placebo, rofecoxib 25 or 50 mg followed by 25 mg every 24 hours as needed, or naproxen sodium 550 mg every 12 hours as needed for up to 3 days. Subjects took all four treatments in a balanced, complete-block, crossover design. Measurements included self-administered questionnaires of analgesic efficacy, spontaneous reports of adverse experiences, physical examinations, and laboratory safety tests.
Results: Rofecoxib 25 and 50 mg provided analgesic efficacy greater than placebo (P 
.006) for the primary endpoint of total pain relief over the first 8 hours. For other efficacy endpoints (sum of the pain intensity difference over the first 8 hours, subject’s global evaluation, peak pain relief, peak pain intensity difference, and time to remedication) both doses of rofecoxib were better than placebo (P .006) and were not distinguishable from naproxen sodium for all efficacy endpoints. All treatments were well tolerated.
Conclusion: Rofecoxib effectively treated primary dysmenorrhea, and cyclooxygenase-2–derived prostanoids play a role in the pathophysiology of primary dysmenorrhea.
Prostaglandin (PG) synthesis in humans is catalyzed by two forms of cyclooxygenase (COX), COX-1 and COX-2, 1,2 which likely mediate distinct biologic processes. COX-1 is constitutively active throughout the body.1–3 In contrast, under basal conditions COX-2 expression is limited, including in the brain4 and kidney,5 but is markedly upregulated by a variety of inflammatory mediators.2 Prostaglandins are involved in the maintenance of gastrointestinal mucosal integrity, so the well-recognized gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs6 is believed to be from inhibition of COX-1 activity.7,8 The therapeutic effects of nonsteroidal anti-inflammatory drugs might be attributable to COX-2 inhibition7,9,10; therefore, agents that specifically inhibit COX-2 are being developed and evaluated because of their potential for efficacy equal to and improved therapeutic index relative to nonsteroidal anti-inflammatory drugs.
Dysmenorrhea is one of the most frequent gynecologic disorders, affecting more than half of menstruating women. With primary dysmenorrhea, women have painful menses without demonstrable pelvic abnormalities.11 Primary dysmenorrhea is believed to be PG mediated. Women with primary dysmenorrhea have significantly higher concentrations of PG in their endometriums and menstrual fluid11–13 than women without primary dysmenorrhea, and the amount of PGF2
in a menstrual fluid correlates with cramps and pain. Medications that inhibit production of prostaglandins, such as nonsteroidal anti-inflammatory drugs, relieve cramps and pain of primary dysmenorrhea.14,15
Although primary dysmenorrhea is characterized by increased production of PG, it is not known whether increased PG production is mediated by COX-1 or COX-2. COX-2 is required for uterine aspects of reproductive processes, including implantation and deciduization,16 but the effect of COX-1 versus COX-2 in normal or abnormal menstruation is unknown. Nonsteroidal anti-inflammatory drugs, such as naproxen sodium, are nonspecific COX-1 and COX-2 inhibitors.2 Development of specific inhibitors of COX-2 allows a pharmacologic means of dissecting the effects of COX-1 versus COX-2–derived prostanoids in primary dysmenorrhea.
Rofecoxib, a 4-methylsulfonylphenyl derivative, inhibits human COX-2 with more than 800 times the selectivity relative to COX-1 in an in vitro assay, using Chinese hamster ovary cell lines expressing COX-1 or COX-2.17 Rofecoxib showed dose-related inhibition of COX-2 but no significant inhibition of COX-1 with single oral doses ranging from 5–1000 mg using ex vivo human whole-blood assays.17 Therefore, rofecoxib is a specific inhibitor of the COX-2 isoform in humans. We conducted a randomized controlled clinical trial in women with primary dysmenorrhea using the COX-2–specific inhibitor, rofecoxib.
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Methods |
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Subjects gave written informed consent, and upon confirmation of eligibility, were dispensed study drugs, diaries, and urine ß-hCG tests. When moderate to severe pain associated with menses developed, subjects took the assigned study drug. During the next 12 hours, subjects assessed pain intensity and degree of pain relief at 11 specified intervals. They were contacted by beeper and reminded of each efficacy evaluation. Subjects who took the drug late in the day or at night were required to complete all specified efficacy evaluations. Subjects received six additional enclosures (each in a separate bottle) of study drug and were permitted to take additional doses of study medication every 12 hours as needed. Each bottle of study medication contained the same number of tablets of active drug or identical placebo.
Subjects returned to the study center to review assessments, new medications, or adverse experiences after completing dosing for each menstrual cycle. Those procedures were followed until subjects took study drugs for four different menstrual cycles (complete-block, crossover design). Subjects were allowed up to five consecutive cycles to complete the required four dosing periods. At final visits, subjects had physical examinations and laboratory tests.
Subjects were randomly assigned to one of four treatment orders (ABCD, BDAC, CADB, or DCBA) by computer-generated allocation schedule in which A was placebo for all doses, B was an initial dose of 25 mg of rofecoxib followed by 25 mg daily as needed (25/25), C was an initial dose of 50 mg of rofecoxib followed by 25 mg daily as needed (50/25), and D was an initial dose of 550 mg of naproxen sodium followed by 550 mg every 12 hours as needed. Masked allocation schedule was generated by an individual not otherwise involved with the study and was concealed from all study participants. The allocation schedule was unmasked when all data had been entered, reviewed, and certified.
Pain was evaluated by subjects at specified times and recorded in the diaries using established rating scales.18 Pain intensity was recorded on a 0 to 3 scale (0 = none to 3 = severe) at baseline and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, and 12 hours after the initial dose. Pain relief was recorded on a 0 to 4 scale (0 = none to 4 = complete). Subjects also recorded the times at which they took additional doses of medication or rescue medication (if study medication did not provide relief). At 8 hours after the initial dose and at the end of the 72-hour treatment period, subjects rated the study drug on a scale of 0 to 4 (0 = poor to 4 = excellent).
Indices of drug efficacy18 were calculated from subjects’ scores, with total pain relief as the summed time-weighted pain relief scores to 8 hours, pain intensity difference from baseline, summed time-weighted pain intensity difference to 8 hours, subject’s global evaluation of study drug at 8 hours, time to pain intensity difference from baseline greater than or equal to 1, peak pain relief, peak pain intensity difference from baseline, percentage of subjects who took rescue medication, and time to rescue medication.
The primary endpoint was total pain relief calculated as the summed time-weighted pain relief scores to 8 hours. With 120 subjects who completed the study, it was designed to have greater than 99% power (based on a two-sided test with significance level 5 .05 and projected within-subject standard deviation [SD] of 8 or 9 units; a pilot study of rofecoxib had an estimated within-subject SD of 7.4 units) to detect a difference of 6 units per 8 hours in total pain relief between any two treatment comparisons. A previous study found a difference of 6 units per 6 hours in total pain relief, calculated as the summed time-weighted pain relief scores to 6 hours, between 550 mg naproxen sodium and placebo.13
Total pain relief was analyzed by a parametric analysis of variance model for a complete-block, crossover design. The analysis of variance model included treatment, baseline pain intensity score, subject (nested within sequence), sequence, period, and carryover as factors. The analysis of variance model, Cox proportional hazards regression model, or generalized estimating equations regression model was used to analyze the other efficacy endpoints as appropriate. Analyses of data were based on the intent-to-treat population, and the primary comparison was between 50 mg of rofecoxib and placebo. The percentage of subjects with clinical and laboratory adverse experiences was compared between each pair of treatments using the pairwise McNemar test.
In the statistical analysis there were statistically significant (P = .032) carryover effects only for the endpoint of peak pain intensity difference from baseline. The analysis of peak pain intensity difference from baseline was done with carryover effects included in the model. Carryover effects were not significant in the analyses of the other efficacy measures, indicating that effects from treatments were not carried over to the next study period. There was no significant treatment-by-baseline pain intensity interaction for any efficacy measure. The factors sequence, subject (nested within sequence), and period were added to the model to adjust for their effects, but assessment of whether treatment effects differed among those factors was not done.
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) and mean pain intensity difference from baseline (data not shown) scores at each evaluation were higher for rofecoxib and naproxen sodium than placebo. There were statistically significant differences from placebo for naproxen sodium at 1 hour and for both rofecoxib groups at 2 hours, which persisted throughout the 12-hour study period.
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. For each endpoint analyzed (except time to pain intensity difference from baseline greater than or equal to 1), both rofecoxib doses and naproxen sodium were statistically superior to placebo and generally similar to each other. A minority of subjects took additional doses. One or more adverse experiences were reported by 13 (11%), 15 (13%), 26 (22%), and 21 (17%) subjects in the placebo, rofecoxib 25/25, 50/25, and naproxen sodium groups, respectively. No serious adverse experiences were reported. There were no statistically significant differences in adverse experiences between treatments. The most common adverse experiences were nausea, upper respiratory infection, and dry mouth. Drug-related adverse experiences were seen in four (3%), seven (6%), 13 (11%), and 11 (9%) subjects in the placebo, rofecoxib 25/25, 50/25, and naproxen sodium groups, respectively (P <.05 for rofecoxib 50/25 versus placebo). The most common drug-related adverse experiences were nausea and dry mouth.
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Discussion |
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Menstrual fluid prostanoid levels of trial subjects were not measured. Previous reports found that dual COX-1 and COX-2 inhibitors inhibited endometrial production of PG and that decreased PG production correlated with cramp and pain relief of primary dysmenorrhea,9,10 so the most parsimonious mechanism to explain our findings is that rofecoxib acts locally in the endometrium. We cannot completely rule out the possibility that inhibition of COX-2 within the central nervous system might affect the analgesic properties of rofecoxib.
Our data supported the hypothesis that the analgesic properties of dual COX-1 and COX-2 inhibitors primarily result from inhibition of COX-2. In other recent studies, rofecoxib had analgesic properties in osteoarthritis19 and analgesic properties similar to dual COX-1 and COX-2 inhibitors for postoperative dental pain.17 Whether inhibition of COX-2 alone is sufficient for analgesic efficacy for other causes of pain will require further studies with specific COX-2 inhibitors such as rofecoxib.
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Footnotes |
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Dr. Morrison, Paul Kotey, and Dr. Seidenberg, as employees of Merck and Co., Inc. may receive stock options as part of their compensation package. This study was supported by Merck Research Laboratories and was conducted at the Clinical Research Offices of SCIREX, a for-profit clinical research organization.
Received January 8, 1999. Received in revised form March 25, 1999. Accepted April 2, 1999.
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2. Smith TJ. Cyclooxygenases as the principal targets for the action of NSAIDs. Rheum Dis Clin North Am 1998;24:501–23.[Medline]
3. DeWitt D. Prostaglandin endoperoxide synthase: Regulation of enzyme expression. Biochim Biophys Acta 1991;1083:121–34.[Medline]
4. Yamagata K, Andreasson KI, Kaufmann WE, Barnes CA, Worley PF. Expression of a mitogen-inducible cyclooxygenase in brain neurons: Regulation by synaptic activity and glucocorticoids. Neuron 1993;11:371–86.[Medline]
5. Kömhoff M, Gröne H-J, Klein T, Seyberth HW, Nüsing RM. Localization of cyclooxygenase-1 and -2 in adult and fetal human kidney: Implication for renal function. Am J Physiol 1997;272: F460–8.
6. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med 1991;15: 787–96.
7. Meade EA, Smith WL, deWitt DL. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other nonsteroidal anti-inflammatory drugs. J Biol Chem 1993;268:6610–4.
8. Bakhle YS, Botting RM. Cyclooxygenase-2 and its regulation in inflammation. Med Inflamm 1996;305–23.
9. Masferrer JL, Zweifel BS, Manning PT, Hauser SD, Leahy KM, Smith WG, et al. Selective inhibition of inducible cyclooxygenase 2 in vivo is anti-inflammatory and non-ulcerogenic. Proc Natl Acad Sci U S A 1994;91:3228–32.
10. Chan CC, Boyce S, Brideau C, Ford-Hutchinson AW, Gordon R, Guay D, et al. Pharmacology of a selective cyclooxygenase-2 inhibitor, L745.337—a novel nonsteroidal anti-inflammatory agent with an ulcerogenic sparing effect in rat and nonhuman primate stomach. J Pharmacol Exp Ther 1995;273:1531–7.
11. Dawood MY. Nonsteroidal anti-inflammatory drugs and reproduction. Am J Obstet Gynecol 1993;169:1255–65.[Medline]
12. Bieglmayer C, Hofer G, Kainz C, Reinthaller A, Kopp B, Janisch H. Concentrations of various arachidonic acid metabolites in menstrual fluid are associated with menstrual pain and are influenced by hormonal contraceptives. Gynecol Endocrinol 1995;9:307–12.[Medline]
13. Nigam S, Benedetto C, Zonca M, Leo-Rossberg I, Lubbert H, Hammerstein J. Increased concentrations of eicosanoids and platelet-activating factor in menstrual blood from women with primary dysmenorrhea. Eicosanoids 1991;4:137–41.[Medline]
14. Chan WY, Dawood MY, Fuchs F. Relief of dysmenorrhea with the prostaglandin synthetase inhibitor ibuprofen: Effect on prostaglandin levels in menstrual fluid. Am J Obstet Gynecol 1979;135:1255–65.
15. Chan WY, Fuchs F, Powell AM. Effects of naproxen sodium on menstrual prostaglandins and primary dysmenorrhea. Obstet Gynecol 1983;61:285–91.
16. Lim H, Paria BC, Das SK, Dinchuk JE, Langenbach R, Trzaskos JM, et al. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell 1997;91:197–208.[Medline]
17. Ehrich EW, Dallob A, de Lepeleire I, van Hecken A, Riendeau D, Yuan W, et al. Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model. Clin Pharmacol Ther 1999;65:336–47.[Medline]
18. Mehlisch DR, Fulmer RI. A crossover comparison of bromfenac sodium, naproxen sodium, and placebo for relief of pain from primary dysmenorrhea. J Womens Health 1997;6:83–92.[Medline]
19. Ehrich E, Schnitzer T, Kivitz A, Weaver A, Wolfe F, Morrison B, et al. MK-966, a highly selective Cox-2 inhibitor, was effective in the treatment of osteoarthritis (OA) of the knee and hip in a 6-week placebo controlled study. J Rheum (in press).
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